Final Report Summary - ER AND INFECTION (ER Function In Virus Infection)
Title:
Stressed-Out! Inflammatory Signaling from the Endoplasmic Reticulum
Project Objectives:
The endoplasmic reticulum (ER) within the cell is responsible for the quality control of all proteins destined for secretion or presentation at plasma membrane. Genetic mutations (acquired or inherited) that result in persistent misfolding and retention of proteins in the ER can cause ER stress. The pathology of such diseases is often understood in terms of the loss of the relevant functional protein, however the contribution of ER stress to the progression of such chronic diseases is not well understood.
ER stress is synonymous with the activation of the unfolded protein response (UPR) that initiates a complex transcriptional and translational program to alleviate stress. However, under prolonged stress, the UPR can initiate apoptosis and is implicated in a number of degenerative diseases such as cystic fibrosis, type II diabetes and Alzheimer’s disease. Our objective was to identify protein determinants of ER stress relevant to disease and determine whether they can instigate inflammatory signaling from the ER.
Approach:
Our approach was to use a number of secretory protein models associated with disease or viral infection. This included:
- Cystic fibrosis conductance regulator (CFTR) and mutations associated with the development of cystic fibrosis (CF).
- The low-density lipoprotein receptor (LDLR) and class II mutations associated with the development of familial hypercholesterolemia (FH) and associated atherosclerosis.
- Viral envelope glycoproteins of influenza A virus (IAV) and human immunodeficiency virus (HIV).
We then assessed these ER-targeted proteins for their corresponding stress and immune signaling profiles, namely early inflammatory responses such as type I interferon signaling. This allowed us to assess ER-dependent inflammatory signaling (or cell autonomous) without secondary (non-cell autonomous) inflammatory responses.
Major findings:
We observed that diverse secretory proteins exhibited distinct stress and immune signaling profiles from the ER. Notably, a strong innate-immune response did not correlate with a strong stress response nor distinguish between “foreign” versus “cellular”-derived proteins. Our results further suggested a degree of specificity in protein-dependent inflammatory signaling from the ER that has not yet been described. Biochemical analysis identified a novel innate-immune signaling pathway that utilizes the UPR to integrate ER stress responses with canonical antiviral immune signaling pathways. Our data strongly suggests that type I interferon signaling is not solely an antiviral response and rather plays a more complex role in cellular stress pathways. Our ongoing research seeks to delineate the mechanisms by which the ER regulates such specificity in both stress and downstream immune signaling events.
Conclusions:
We conclude that protein-dependent ER stress can initiate a type I interferon response and that this pathway could play a significant role in the chronic inflammation observed in many genetic diseases that cause protein misfolding and/or aggregation.
Scientific/Clinical Impact:
Endoplasmic reticulum (ER) stress is a common feature of diverse chronic inflammatory diseases including cystic fibrosis, diabetes and many auto-immune or malignant disorders. Our identification of a novel intersection between ER stress and a major inflammatory signaling pathway suggests that targeting stress may dramatically reduce inflammation and therefore slow tissue/organ degeneration in disease.
Socio-Economic Impact:
Chronic inflammatory diseases are placing an increasing burden on the public health system particularly in context of ageing populations within the EU. Our research aims to inform targeted drug design to improve outcomes, and therefore the independence, of patients suffering from these diseases.
Stressed-Out! Inflammatory Signaling from the Endoplasmic Reticulum
Project Objectives:
The endoplasmic reticulum (ER) within the cell is responsible for the quality control of all proteins destined for secretion or presentation at plasma membrane. Genetic mutations (acquired or inherited) that result in persistent misfolding and retention of proteins in the ER can cause ER stress. The pathology of such diseases is often understood in terms of the loss of the relevant functional protein, however the contribution of ER stress to the progression of such chronic diseases is not well understood.
ER stress is synonymous with the activation of the unfolded protein response (UPR) that initiates a complex transcriptional and translational program to alleviate stress. However, under prolonged stress, the UPR can initiate apoptosis and is implicated in a number of degenerative diseases such as cystic fibrosis, type II diabetes and Alzheimer’s disease. Our objective was to identify protein determinants of ER stress relevant to disease and determine whether they can instigate inflammatory signaling from the ER.
Approach:
Our approach was to use a number of secretory protein models associated with disease or viral infection. This included:
- Cystic fibrosis conductance regulator (CFTR) and mutations associated with the development of cystic fibrosis (CF).
- The low-density lipoprotein receptor (LDLR) and class II mutations associated with the development of familial hypercholesterolemia (FH) and associated atherosclerosis.
- Viral envelope glycoproteins of influenza A virus (IAV) and human immunodeficiency virus (HIV).
We then assessed these ER-targeted proteins for their corresponding stress and immune signaling profiles, namely early inflammatory responses such as type I interferon signaling. This allowed us to assess ER-dependent inflammatory signaling (or cell autonomous) without secondary (non-cell autonomous) inflammatory responses.
Major findings:
We observed that diverse secretory proteins exhibited distinct stress and immune signaling profiles from the ER. Notably, a strong innate-immune response did not correlate with a strong stress response nor distinguish between “foreign” versus “cellular”-derived proteins. Our results further suggested a degree of specificity in protein-dependent inflammatory signaling from the ER that has not yet been described. Biochemical analysis identified a novel innate-immune signaling pathway that utilizes the UPR to integrate ER stress responses with canonical antiviral immune signaling pathways. Our data strongly suggests that type I interferon signaling is not solely an antiviral response and rather plays a more complex role in cellular stress pathways. Our ongoing research seeks to delineate the mechanisms by which the ER regulates such specificity in both stress and downstream immune signaling events.
Conclusions:
We conclude that protein-dependent ER stress can initiate a type I interferon response and that this pathway could play a significant role in the chronic inflammation observed in many genetic diseases that cause protein misfolding and/or aggregation.
Scientific/Clinical Impact:
Endoplasmic reticulum (ER) stress is a common feature of diverse chronic inflammatory diseases including cystic fibrosis, diabetes and many auto-immune or malignant disorders. Our identification of a novel intersection between ER stress and a major inflammatory signaling pathway suggests that targeting stress may dramatically reduce inflammation and therefore slow tissue/organ degeneration in disease.
Socio-Economic Impact:
Chronic inflammatory diseases are placing an increasing burden on the public health system particularly in context of ageing populations within the EU. Our research aims to inform targeted drug design to improve outcomes, and therefore the independence, of patients suffering from these diseases.
